Defective lysosomal proteolysis and axonal transport are early pathogenic events that worsen with age leading to increased APP metabolism and synaptic Abeta in transgenic APP/PS1 hippocampus

Abstract

BackgroundAxonal pathology might constitute one of the earliest manifestations of Alzheimer disease. Axonal dystrophies were observed in Alzheimer’s patients and transgenic models at early ages. These axonal dystrophies could reflect the disruption of axonal transport and the accumulation of multiple vesicles at local points. It has been also proposed that dystrophies might interfere with normal intracellular proteolysis. In this work, we have investigated the progression of the hippocampal pathology and the possible implication in Abeta production in young (6 months) and aged (18 months) PS1(M146L)/APP(751sl) transgenic mice.ResultsOur data demonstrated the existence of a progressive, age-dependent, formation of axonal dystrophies, mainly located in contact with congophilic Abeta deposition, which exhibited tau and neurofilament hyperphosphorylation. This progressive pathology was paralleled with decreased expression of the motor proteins kinesin and dynein. Furthermore, we also observed an early decrease in the activity of cathepsins B and D, progressing to a deep inhibition of these lysosomal proteases at late ages. This lysosomal impairment could be responsible for the accumulation of LC3-II and ubiquitinated proteins within axonal dystrophies. We have also investigated the repercussion of these deficiencies on the APP metabolism. Our data demonstrated the existence of an increase in the amyloidogenic pathway, which was reflected by the accumulation of hAPPfl, C99 fragment, intracellular Abeta in parallel with an increase in BACE and gamma-secretase activities. In vitro experiments, using APPswe transfected N2a cells, demonstrated that any imbalance on the proteolytic systems reproduced the in vivo alterations in APP metabolism. Finally, our data also demonstrated that Abeta peptides were preferentially accumulated in isolated synaptosomes.ConclusionA progressive age-dependent cytoskeletal pathology along with a reduction of lysosomal and, in minor extent, proteasomal activity could be directly implicated in the progressive accumulation of APP derived fragments (and Abeta peptides) in parallel with the increase of BACE-1 and gamma-secretase activities. This retard in the APP metabolism seemed to be directly implicated in the synaptic Abeta accumulation and, in consequence, in the pathology progression between synaptically connected regions.

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

“…3, A and B). As expected, pharmacological inhibition of ␥-secretase by the specific inhibitor N-[N- (3,5difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester efficiently reduced the generation of AICD (Fig. 3, A and B).…”

“…The subsequent cleavage of APP-CTF␣ by ␥-secretase results in secretion of a small peptide called p3 (2). It is important to note that APP is also metabolized by additional pathways, including proteasomal and lysosomal degradation (3)(4)(5).…”

Phagocytic clearance of presynaptic dystrophies by reactive astrocytes in Alzheimer's disease

“…Therefore, transcellular degradation of neuronal dystrophies by astrocytes might directly support neuron survival or, alternatively, it might reduce the Aβ release from dystrophic presynaptic elements. In this sense, presynaptic dystrophies are sites of APP accumulation and putative Aβ release (Sanchez‐Varo et al, 2012; Torres et al, 2012) and, as recent studies indicate, the accumulation of BACE1 in presynaptic dystrophies surrounding plaques causes increased cleavage of APP and Aβ generation, which could lead to an exacerbation of amyloid pathology in AD (Sadleir et al, 2016; Torres et al, 2012). Alternatively, insulating dystrophies from the normal tissue might also decrease the probability of possible adverse inflammatory effects.…”

“…These bigenic mice were obtained (see Blanchard et al, 2003) by crossing homozygous PS1 mice (expressing human mutant PS1[M146L] under HMGCoA reductase promoter) to hemizygous APP751SL mice (expressing human mutant APP751 carrying the Swedish [KM670/671NL] and London [V717I] mutations under the control of the Thy1 promoter). We have previously characterized this APP/PS1 transgenic model (Baglietto‐Vargas et al, 2010; Jimenez et al, 2008; Ramos et al, 2006; Sanchez‐Varo et al, 2012; Torres et al, 2012; Trujillo‐Estrada et al, 2014). Age‐matched non‐transgenic mice (WT) of the same genetic background (C57BL:6) were used as controls.…”

Axonal transport of cytoskeleton and cytoskeleton regulatory cargo proteins in neurodegenerative disorders

“…Defective axonal transport has been linked to a number of diseases, i.e. : a) adultonset neurodegenerative diseases, AONDs 4,5 , a set of dysfunctional and degenerative disorders affecting different populations of neurons; b) motor neuron disorders such as: amyotrophic lateral sclerosis 6,7 , distal hereditary motor neuropathy 8 , spinal muscular atrophy 7 , hereditary spastic paraplegia 9 ; c) Alzheimer's, Parkinson's and Huntington's and related disorders [10][11][12][13] ; and d) Charcot-Marie-Tooth disease (CMT), a heterogeneous group of hereditary motor and sensory neuropathies 1,14 . Recently, disturbances in axonal transport have also been shown in neurological complications of diabetes [15][16][17][18][19] .…”